Poly(ethylene glycol) methacrylate microgels, preparation method and uses

ABSTRACT

The invention relates to poly(oligo(ethylene glycol) methacrylate) microgels, to the process for preparing same and the uses thereof in various fields of application such as optics, electronics, pharmacy and cosmetics. 
     These microgels have the advantage of being monodisperse, pH-responsive and temperature-responsive. They can carry magnetic nanoparticles or biologically active molecules. These microgels may also form transparent films, which have novel optical and electromechanical properties.

This application is a continuation application of U.S. application Ser.No. 16/359,657 filed on Mar. 20, 2019, which is a continuationapplication of U.S. application Ser. No. 15/541,999 filed on Jul. 6,2017, now issued as U.S. Pat. No. 10,287,403, which is a national stageapplication under 35 USC 371 of PCT Application No. PCT/FR2015/050019having an international filing date of Jan. 6, 2015, the entiredisclosures of each are hereby incorporated by reference in theirentirety.

The invention relates to poly(oligo-(ethylene glycol) methacrylate)microgels, to the process for preparing same in an aqueous medium and tothe uses thereof in various fields of application such as optics,electronics, sensors, cosmetics, pharmacy and medical diagnosis.

These microgels have the advantage of being monodisperse, pH-responsiveand temperature-responsive and of being able to incorporate organicmolecules or inorganic particles. Films prepared from colloidalsolutions of these microgels optionally filled with inorganicnanoparticles have very advantageous optical and electromechanicalproperties.

PRIOR ART

There are several chemistries of temperature-responsive microgels. Themain ones are based on poly(N-isopropylacrylamide) (PNIPAM), and lesscommonly on poly(N-vinylcaprolactam) (PVCL) or on poly(oligo(ethyleneglycol) methacrylate).

The various pathways for synthesizing poly(oligo(ethylene glycol)methacrylate) microgels which have been described in the literatureinvolve combinations of monomers such as the di(ethylene glycol) methylether methacrylate monomer (M(EO)₂MA, somewhat hydrophobic), and thepenta(ethylene glycol) methyl ether methacrylate monomer (M(EO)₅MAsomewhat hydrophilic).

The synthesis of a temperature-responsive and pH-responsive microgel,consisting of a temperature-responsive core based onP(M(EO)₂MA-co-M(EO)₅MA) and of a shell based on a mixture ofpoly(oligo(ethylene glycol) methacrylate) and poly(acrylic acid)(P(M(EO)₂MA-co-M(EO)₅MA-co-AA)) has been described by Chi, C., T. Cai,and Z. Hu, Oligo(ethylene glycol)-Based Thermoresponsive Core-ShellMicrogels. Langmuir, 2009. 25: p. 3814-3819. These microgels have acore/shell structure with a hydrophobic core and a hydrophilic shell.

It has been suggested to incorporate biologically active molecules intomicrogels based on poly(oligo(ethylene glycol) methacrylate).

For example, a temperature-responsive microgel consisting of apoly(M(EO)₂MA) core and of a P(M(EO)₂MA-co-M(EO)₅MA) shell and ofpoly(M(EO)₂MA-co-OEGMA) nanocapsules obtained by grafting the polymeronto a sacrificial silica particle have been proposed for the deliveryof an active principle respectively by Zhou, et al., Engineeringoligo(ethylene glycol)-based thermosensitive microgels for drug deliveryapplications. Polymer, 2010. 51: p. 3926-3933; and by Wang, et al.,Preparation of biocompatible nanocapsules with temperature-responsiveand bioreducible properties, Journal of Materials Chemistry, 2011. 21:p. 15950.

Known hybrid (or nanocomposite) temperature-responsive microgelscontaining inorganic nanoparticles are microgels based onpoly(N-isopropylacrylamide) (PNIPAM). These microgels have the drawbackof not being biocompatibie.

A first approach for preparing these materials consists in synthesizingthe microgels in the presence of the nanoparticles. This strategy makesthe manufacture of these hybrid microgels difficult due to thecomplexity of the polymerization. The proportion of nanoparticlesincorporated is generally small and the microgels are polydisperse.Furthermore, it generally results in a core-shell type architecturewithin which the nanoparticles are uniformly distributed.

A second approach consists in synthesizing, firstly, thetemperature-responsive microgels functionalized by ionic groups. Next,the inorganic nanoparticles are incorporated by coprecipitation of theprecursor salts of the nanoparticles. Application WO 2004/081072describes for example PNIPAM microgels having sodium acrylate (—COO⁻Na⁺) anionic units and the in situ coprecipitation of precursor salts ofvarious nanoparticles such as magnetic (Fe₃O₄) particles, gold (Au)particles, and quantum dot (CdTe, CdS) particles.

A third approach consists in incorporating the inorganic nanoparticlesby solvent transfer. Hydrophobic inorganic nanoparticles are synthesizedand dispersed in an organic phase. The temperature-responsive microgelsare added to the solution containing the nanoparticles then everythingis transferred into aqueous solution, which encapsulates thenanoparticles in the microgels. This method has been the subject of apatent using poly(N-isopropylacrylamide) microgels and Quantum dot (CdS)nanoparticles for applications in photoluminescence (U.S. Pat. No.7,914,710).

A fourth and final approach consists in synthesizing microgels bearingionic charges and in adsorbing nanoparticles of opposite charges at thesurface of the microgel. The preparation ofpoly(styrene-co-N-isopropylacrylamide) latex having 2-aminoethylmethacrylate (AEMA) cationic groups has been described in application WO1997/045202. Magnetic γ-Fe₂O₃ nanoparticles negatively charged at thesurface were adsorbed at the surface of the lattices by electrostaticinteraction. The nanoparticles were then trapped in the structure bysynthesis of a new outer shell of PNIPAM at the surface of the hybridlattices.

More recently, nanoparticles bearing a positive charge (TiO₂) have beenincorporated into a PNIPAM microgel structure charged by unitscomprising an acrylate (COO⁻) group (U.S. Pat. No. 8,158,005).

The use of microgels, especially temperature-responsive microgels thathave magnetic properties, requires in certain fields their preparationin the form of thin films.

The formation of thin films composed of microgels predispersed in anaqueous phase is a difficult synthesis process since it necessitatesreconciling two conflicting factors. Microgels dispersed in an aqueousphase are stabilized by repulsive charges that prevent the microgelsfrom aggregating or settling. However, the microgels must interact withone another to form layers of microgels in order to form a film. Severalprocesses have had to be developed in order to form them.

A first process for self-assembling microgels on a modified surfaceconsists in anchoring microgels to the surface of a substrate pretreatedin order to create ionic charges on its surface. The microgels haveionic groups generally derived from the polymerization initiator or froman ionic comonomer. The microgels may be anchored to the surface of asubstrate by electrostatic interaction with oppositely charged groups.This technique makes it possible to deposit a thin layer of microgel onthe substrate (monolayer technique), but it is also possible to multiplythese layers by successive surface treatments (Layer-by-Layertechnique). Microgels based on poly(N-isopropylacrylamide-co-acrylicacid) or P(NIPAM-co-AA) have been deposited according to this techniqueon substrates grafted by 3-aminopropyltrimethoxysilane (APTMS) groups.After each layer of microgel, a polymer having positive charges(poly(allylamine hydrochloride) PAH or polyethylene imine) PEI) wasadded to the modified substrate in order to regenerate the positivecharges for a lower pH at the acidity constant of the amines.

The films of microgels deposited on the substrate have been used for thedelivery of an active principle such as insulin for the treatment ofdiabetes (Nolan, C. M., M. J. Serpe, and L. A. Lyon, Thermally ModulatedInsulin Release from Microgel Thin Films. Biomacromolecules, 2004. 5(5):p. 1940-1946) or doxorubicin for the treatment of cancerous cells(Serpe, M. J., et al., Doxorubicin Uptake and Release from Microgel ThinFilms. Biomacromolecules, 2005. 6(1): p. 408-413).

This technique has the advantage of controlling the parameters inherentto the production of a thin film of microgels (such as the filmthickness and the structuring of the microgels). The drawback of thisprocess lies in its production complexity which requires the use ofparticular microgels (charged microgels) and pretreated substrates. Thisprevents any direct use of the microgels on any surface.

A second process for producing a hydrogel film that encapsulatescolloidal particles consists in encapsulating the particles in ahydrogel in order to form a flexible and wet film. This process ismainly studied for photonic applications. The idea is to combine theoptical properties of assembled particles with the mechanical propertiesof the hydrogels in the wet state. Some examples are described in theliterature and mainly use polystyrene) particles in the form of hardspheres. E. Tian et al. have assembled poly(styrene-co-methylmethacrylate-co-acrylic acid) particles as several structured layers andhave encapsulated everything in a polyacrylamide) hydrogel (Tan, E., etal., Colorful humidity sensitive photonic crystal hydrogel. Journal ofMaterials Chemistry, 2008.18: p. 1116-1122). The combination of the twoentities has made it possible to develop photonic hydrogels. Morerecently, H. Jiang et al. also encapsulated polystyrene) particles in apolyvinyl alcohol) or PVA hydrogel (Jiang, H., et al., Photonic crystalpH and metal cation sensors based on poly (vinyl alcohol) hydrogel. NewJournal of Chemistry, 2012. 36: p. 1051-1056).

More recently, H. Kim et al. assembled magnetic particles of iron oxide(Fe₃O₄) coated with silica oxide (SiO₂) under the effect of a magneticfield and encapsulated this assembly in a mixture of polyethyleneglycol) diacrylate monomer and a photoinitiator. The photopolymerizationof the mixture makes it possible to set the particles in a polyethyleneglycol acrylate) resin. The magnetic particles set in the bulk havephotonic properties that may be defined by the magnetic field applied(US 2012/0028834). This technique has the advantage of producing moreflexible microgel films since the latter are supported by a “soft”hydrogel in solution, and not a solid support. However, the productionof these films of particles remains complex and various polymerizationsteps are necessary, which prevents any spontaneous self-assembly duringa direct use of the particles.

A third process for forming microgel films consists in adding reactivefunctions to the surface of the microgels. This functionality isprovided by addition of a comonomer during the synthesis of themicrogels. These reactive functions may either form covalent bonds withone another, or form covalent bonds by reaction with another entity. Itis then possible to form crosslinking points between each microgel, thewhole thing giving a film composed of microgels that are chemicallybound to one another. This self-assembly process is mainly studied forphotonic applications. The self-assembly process depends on the type offunctionality added during the synthesis of the microgels. A vastmajority of these studies have focused on the assembly of PNIPAM-basedmicrogels.

A first approach consists in adding poly(acrylic acid) (or PAA) withinPNIPAM microgels. The self-assembly of the microgels takes place owingto weak interactions between the carboxylic acid functions of the PAA.The sum of the interactions makes it possible to self-assemble themicrogels and to gel the medium.

A second approach that consists in creating covalent bonds has also beenproposed, either by addition of a crosslinker to the solution of PNIPAMmicrogels, or by polycondensation of PNIPAM-co-NMA microgels (NMA:N-methylol acrylamide or N-hydroxymethyl acrylamide). The microgels areself-assembled by simple drying of a dispersion of microgels. Theformation of the film requires an additional step of thermalpost-polymerization of the crosslinker or of thermal and acid-basecatalyzed condensation of the NMA.

One study used oligo(ethylene glycol) methacrylate derivative microgelshaving surface-polymerizable functions. These microgels were crosslinkedby UV photopolymerization during their assembly for photonicapplications (US 2010/0076105). However, the film formation requires avery long drying time of around several weeks.

The objective of the invention is to propose an oligo(ethylene glycol)methacrylate microgel that has at least one of the following advantagesrelative to the microgels of the prior art: monodisperse; pH-responsive;biocompatible; capable of forming hybrid (or nanocomposite) microgels byadsorption of oppositely charged nanoparticles; capable ofself-assembling in several layers by simple drying process; capable offorming a transparent film; capable of forming a cohesive and elasticfilm; in the form of a film, capable of generating an electric potentialvia compression effect; in the form of a film, capable of diffractinglight thus generating a color.

It has been discovered within the context of the present invention thatcertain poly(oligo(ethylene glycol) methacrylates) have a highfilm-forming potential by evaporation of water at ambient temperature.In particular, the invention proposes for the first time theself-assembly of magnetic hybrid microgels in the form of a thin filmhaving structuring properties.

The microgel films of the invention have the advantage of beingcompletely self-supported. Since the microgels are not encapsulated orsupported, during the film formation the interaction between themicrogels and the substrate on which they are deposited, for example theskin, is maximal. The films are obtained by simple drying at ambienttemperature and no radical initiator is necessary. The microgels of theinvention optionally containing nanoparticles are capable ofself-assembling in several layers in order to form a transparent film.

It has also been discovered, within the context of the presentinvention, that the poly(oligo(ethylene glycol) methacrylate) microgelsare polyelectrolyte materials capable of generating an electric field bymechanical action.

DESCRIPTION OF THE INVENTION

The invention relates to poly(oligo(ethylene glycol) methacrylate)microgels endowed with colloidal properties and also a responsiveness tovariations of temperature and/or pH in water, owing to the presence ofoptionally salified —COOH groups.

Within the meaning of the invention a “microgel” is understood to be acrosslinked polymer in the form of a spherical particle having a sizethat varies from 100 nm to 500 nm in the dry state (i.e. containing lessthan 2% by weight of water), preferably between 350 and 450 nm, morepreferably of the order of 400 nm. The microgel of the invention is amicrohydrogel in the sense that it is capable of being obtained by aprocess of aqueous phase copolymerization of several monomers. Themicrogel of the invention does not have a core/shell structure: themonomers that form it are distributed uniformly throughout the volume ofthe particle, which gives it particular properties.

The microgels of the invention may have the advantage of simultaneouslybeing monodisperse, temperature-responsive, pH-responsive andbiocompatible. The microgels of the invention may simultaneously betemperature-responsive and biocompatible, unlike thetemperature-responsive microgels of the prior art which are generallystructures based on poly(alkylacrylamide).

The microgels of the invention have the novelty of comprising a mixtureof branched ethylene oxide repeat units and units comprising acarboxylic acid (—COOH) or carboxylate (—COO⁻) group, the content ofwhich it is possible to vary depending on the targeted applications.These groups give the microgels the pH-responsive property.

A first subject of the invention is thus microgels obtainable by aqueousphase precipitation polymerization of the following three monomers:

-   -   di(ethylene glycol) methyl ether methacrylate (M(EO)₂MA),    -   an oligo(ethylene glycol) methyl ether methacrylate        (M(EO)_(n)MA) n ranging from 3 to 12,    -   a monomer of formula CR₁R₂═CR₃R₄ in which R₁, R₂, R₃ and R₄        represent a hydrogen, a halogen or a hydrocarbon group, at least        one of the four groups comprising a —COOH or —COO⁻M⁺ group, M⁺        representing a cation,

in the presence of a crosslinking agent.

In the remainder of the text, the term “—COOH” denotes the —COOH acidform or —COO⁻M⁺ salified form, for simplification.

M(EO)₂MA represents for example 50 mol % to 90 mol % of the total numberof moles of the monomers, M(EO)_(n)MA preferably represents 10 to 50 mol% of the total number of moles of the monomers and the monomer offormula CR₁R₂═CR₃R₄ preferably represents 0.1 mol % to 20 mol % of thetotal number of moles of the monomers, the sum of these three contentsbeing equal to 100%.

The molar ratio between M(EO)₂MA and M(EO)_(n)MA is preferably between1:1 and 20:1, for example between 5:1 and 10:1. Within the meaning ofthe invention the expression “between” excludes the numerical limitsthat succeed it. On the other hand, the expression “ranging from . . .to” includes the stated limits.

The oligo(ethylene glycol) methyl ether methacrylate has a formula(M(EO)_(n)MA) where n ranges from 3 to 12. The number n can range from 7to 9, or from 7 to 8, or from 8 to 10. The number n can also be 9. Themolecular weight Mn of the oligo(ethylene glycol) methyl ethermethacrylate can be 475 g/mol.

The number of moles of monomer of formula CR₁R₂═CR₃R₄ may be between 0and 20 mol %, for example ranging from 0.1 to 5 mol % of the totalnumber of total moles of the three monomers.

According to one embodiment, M(EO)₂MA represents for example 80 to 90mol % of the total number of moles of the three monomers, M(EO)_(n)MApreferably represents 5 to 15 mol % of the total number of moles of themonomers and methacrylic acid preferably represents 0.1 to 10 mol % ofthe total number of moles of the monomers, the sum of these threecontents being equal to 100%.

The monomer of formula CR₁R₂═CR₃R₄ is preferably such that R₁ and R₂each represent a hydrogen, R₃ represents H or an alkyl group, preferablya C1-C6 alkyl group, optionally substituted with —OH or —COOH, and R₄represents, independently of R₃, the —COOH group or an alkyl group,preferably a C1-C6 alkyl group, optionally substituted with —OH or—COOH. The alkyl group may be methyl, ethyl or n-butyl. According to oneparticular embodiment, R₁ and R₂ each represent a hydrogen and R₃ and R₄independently represent —H, —COOH, or —CH₂—COOH.

The monomer of formula CR₁R₂═CR₃R₄ may for example be chosen from methylacrylic, methyl methacrylic, ethyl acrylic, ethyl methacrylic, n-butylacrylic and n-butyl methacrylic acids.

According to one embodiment, the monomer of formula CR₁R₂═CR₃R₄ may bemethacrylic acid or itaconic acid. Acrylic acid may be excluded from thedefinition of the monomer of formula CR₁R₂═CR₃R₄ in certain cases.

The crosslinking agent may be selected from the group consisting ofoligo(ethylene glycol) diacrylate comprising from 1 to 10 ethyleneglycol units, 1,3-butanediol diacrylate, 1,4-butanediol diacrylate,1,6-hexanediol diacrylate, pentaerythritol diacrylate monostearate,glycerol 1,3-diglycerolate diacrylate, neopentyl glycol diacrylate,polypropylene glycol) diacrylate, 1,6-hexanediol ethoxylate diacrylate,trimethylolpropane benzoate diacrylate, ethylene glycol dimethacrylate,1,3-butanediol dimethacrylate, 1,4-butanediol dimethacrylate,1,6-hexanediol dimethacrylate, glycerol dimethacrylate,N,N-divinylbenzene, N,N-methylenebisacrylamide,N,N-(1,2-dihydroxyethylene)bisacrylamide, polyethylene glycol)diacrylamide, allyl disulfide, bis(2-methacryloyl)oxyethyl disulfide andN,N-bis(acryloyl)cystamine.

The crosslinking agent represents for example from 1 to 5 mol % of thetotal number of moles of the three monomers.

The monomers used are preferably di(ethylene glycol) methyl ethermethacrylate (M(EO)₂MA, Mn 250 g.mol⁻¹), oligo(ethylene glycol) methylether methacrylate (Mn 475 g.mol⁻¹), methacrylic acid (MAA).

The crosslinking agent is for example oligo(ethylene glycol) diacrylatecomprising 4 to 5 ethylene oxide units (OEGDA, Mn 250 g.mol⁻¹). Thechemical structures of the preferred monomers and crosslinking agent arerepresented in FIG. 1.

The mean size of a microgel of the invention may vary depending onwhether it is dry or in aqueous solution: thus, a microgel in the drystate may reach four times its initial size when it is placed in aqueoussolution at 20° C. The mean size of a microgel of the invention in thedry state may range from 100 to 1000 nm. The hydrodynamic radialdistribution function of the microgels measured at an angle of 60° andat a temperature of 20° C., is advantageously less than 1.1, which givesthe microgels the quality of being monodisperse.

The microgels of the invention may comprise organic or inorganicparticles: in this case they are commonly known as hybrid microgels. Theparticles introduced preferably have a size of between 1 and 150 nm, forexample between 5 and 50 nm, and are known as nanoparticles. Thenanoparticles may or may not be magnetic.

A second subject of the invention are monodisperse,temperature-responsive and magnetic hybrid microgels based onpoly(oligo(ethylene glycol) methacrylate) containing magneticnanoparticles, and a process for preparing these hybrid microgels.

Certain monodisperse, temperature-responsive and magnetic hybridmicrogels based on poly(oligo(ethylene glycol) methacrylate) of theinvention are obtained from at least two monomers:

-   -   di(ethylene glycol) methyl ether methacrylate (M(EO)₂MA), and    -   an oligo(ethylene glycol) methyl ether methacrylate        (M(EO)_(n)MA) n being an integer ranging from 3 to 12, and        optionally in the presence of a third monomer:    -   a monomer of formula CR₁R₂═CR₃R₄ in which R₁, R₂, R₃ and R₄        represent a hydrogen, a halogen or a hydrocarbon group, on        condition that at least one of the four groups comprises a —COOH        or —COO⁻M⁺ group, such that M⁺ represents a cation.

A process for preparing monodisperse, temperature-responsive andmagnetic hybrid microgels based on poly(oligo(ethylene glycol)methacrylate) of the invention consists in:

-   -   preparing a colloidal dispersion of nanoparticles that are        positively charged at their surface and that are placed in        aqueous solution,    -   preparing an aqueous colloidal dispersion of microgels as        claimed in one of claims 1 to 4,    -   mixing the two colloidal dispersions and adjusting the pH above        the isoelectric point of the nanoparticles.

According to one embodiment, the nanoparticles are positively charged attheir surface when they are placed in aqueous solution to the extentthat the hybrid microgels of the invention may be prepared by simplemixing of two colloidal dispersions: a first colloidal dispersion ofmicrogels and a second colloidal dispersion of nanoparticles. The keyparameters enabling the success of this process lie, on the one hand, inthe addition of carboxyl or carboxylate groups distributed homogeneouslywithin the microgel and, on the other hand, in the positive surfacecharge of the nanoparticles. Everything makes it possible to encapsulatethe nanoparticles within the microgel in a controlled manner, whilepreserving the colloidal and temperature-responsive properties of thefinal material. The hybrid architecture of the microgels and also theirtemperature-sensitive properties are demonstrated in this invention. Theincorporation of the nanoparticles within the microgels is firstlydemonstrated with a large and quantitative content of encapsulatedmagnetic nanoparticles (filler contents tested ranging from 0 to 33 wt %of nanoparticles per hybrid microgel). The temperature-responsiveproperties of the hybrid microgels in aqueous solution are alsodemonstrated irrespective of the magnetic nanoparticle filler content.

According to one embodiment, the nanoparticles are pigments, dyes orsunscreens commonly used in the optics, cosmetics, agri-food or pharmacyfields.

The particles may comprise at least one metal or one metal oxide. Themetal may be gold, silver, tin, titanium, copper or aluminum. The metaloxide may be selected from the group consisting of iron, titanium, zinc,chromium and tin oxides.

The particles comprise for example at least one of the followingcompounds: TiO₂, Fe₂O₃, TiFe₂O₅, Ti-suboxides, Fe₃O₄, Cr₂O₃, ZrO₂, ZnO,SnO₂, Sn(Sb)O₂.

According to one embodiment, the nanoparticles are magneticnanoparticles of iron oxide (Fe₂O₃, maghemite) having a size between 1and 150 nm, for example between 6 and 30 nm.

The magnetic nanoparticles may be synthesized by coprecipitation ofmetal salts (Fe²⁺ and Fe³⁺) in the aqueous phase, then oxidation inorder to produce magnetic nanoparticles (γ-Fe₂O₃) stabilized in solutionby positive charges. The process for the synthesis of maghemitenanoparticles may be that developed by Massart, R., Preparation ofaqueous magnetic liquids in alkaline and acidic media. IEEE Trans.Magn., 1981. 17(2): p. 1247-1248.

The preparation of temperature-responsive hybrid microgels based onpoly(oligo(ethylene glycol) methacrylate) and nanoparticles maypreferably be earned out by a process of mixing the two constituents inthe form of colloidal dispersions. The nanoparticles placed in aqueoussolution are capable of being positively charged at the surface whenthey are brought into contact with the microgels. The stability of thehybrid microgels is obtained by an increase in pH above the isoelectricpoint of the inorganic nanoparticles while preserving the encapsulationof the nanoparticles.

This process has the advantage of being simple to implement. Thehomogeneous distribution of the carboxylic acid or carboxylate groupswithin the microgel and the selection of nanoparticles that arepositively charged at the surface makes it possible to encapsulate thenanoparticles within the microgel in a controlled manner, whilepreserving the colloidal and temperature-responsive properties of thefinal material.

The hybrid microgels of the invention may contain up to 50% by weight,in particular up to 35% by weight of nanoparticles without losing theircolloidal, pH and temperature-responsive properties. The content ofnanoparticles per hybrid microgels may be determined bythermogravimetric analysis (TGA).

The microgels described above optionally comprising nanoparticles arecapable of self-assembling in order to form a film consisting of one ormore layers of microgels, by a process of drying or evaporating anaqueous suspension of said microgels.

The films formed are cohesive and elastic. The microgels of theinvention may thus be used as film-forming agent in cosmeticcompositions, so as to improve the hold of these compositions on keratinmaterials. After drying, the films do not re-disperse when they areimmersed in water.

The microgels and the films that they form may generate an electricpotential via compression effect (Donnan effect). The films are preparedfrom microgels having ionic sites derived from carboxylate (COO⁻)functions. These ionic sites are constrained in the structure and createpolarizations within the microgel (e.g. polyelectrolyte microgels). Whenthe film is subjected to a pressure, a movement of the counterions helpsto create a polarization within the film that generates an electricpotential difference between the surface and the bulk of the film. Theinventors have found that the presence of methacrylic acid improves theelectromechanical properties of the films.

The self-assembly of monodisperse microgels also enables a diffractionof light thus generating a color. The photonic properties may beadjusted by the very composition of the microgels.

The monodisperse microgels of the invention may self-assembleperiodically in the form of colloidal crystals. This particularself-assembly enables the diffraction of incident light and thusgenerates a color that can be observed depending on the viewing angle.This effect varies as a function of the composition of the microgels: a)the drying of a dispersion of microgels without nanoparticles inducesthe formation of a completely transparent colorless dry film that doesnot diffract light. Whereas this same film diffracts light in the wetstate with colors that can be observed in solution, b) the drying of adispersion of microgels containing magnetic nanoparticles (hybridmicrogels) leads to the formation of a transparent, colored (brown) dryfilm that diffracts light. Consequently the film is brown at a viewingangle of 90° (color derived from the magnetic nanoparticles) and changescolor in reflection at smaller viewing angles.

The presence of magnetic nanoparticles within the microgels makes itpossible to orient the microgels with the aid of a permanent magnet andto improve the mechanical properties of the films. During the drying ona given surface, the temperature-responsive and magnetic microgels maybe guided to and concentrated at a precise point with the aid of apermanent magnet. This has the effect of varying the thickness and thecolor of the films (darker or lighter brown tint). Furthermore, themagnetic nanoparticles improve the mechanical properties of the films ina wet medium thus making it possible to exert greater compression on thefilm.

All of these properties make it possible to envisage the use of themicrogels of the invention and of the films that they form for thepreparation of cosmetic or pharmaceutical products. These products maystimulate the skin by generating an electric current and optionallydelivering a biologically active molecule via compression effect. Thebiologically active molecule may be encapsulated in microgels or bepresent in the product.

Another subject of the invention is therefore a cosmetic orpharmaceutical product consisting of or containing the microgels asdescribed above and optionally at least one compound chosen from thegroup consisting of surfactants, oils, biologically active products,pigments and dyes.

The microgel of the invention may contain all sorts of ingredients orexcipients used in the cosmetic and pharmaceutical field, preferablypigments based on iron oxide or biologically active substances.

The microgels of the invention may be synthesized by a precipitationpolymerization process, using monomers pre-dissolved in aqueoussolution.

The present invention also relates to a process for the precipitationpolymerization of a polyethylene glycol) methacrylate microgel asdescribed above, comprising a step of bringing into contact in theaqueous phase, in the presence of a crosslinking agent, the threemonomers described above, at a temperature of between 40° C. and 90° C.The process of the invention does not require the presence of asurfactant such as SDS (dodecyl sulfate sodium).

The polymerization of the monomers may be initiated by addition of awater-soluble radical initiator, for example potassium persulfate (KPS)at a temperature of between 40° C. and 90° C., preferably of the orderof 70° C.

It is preferred to add an aqueous solution of the monomer of formulaCR₁R₂═CR₃R₄ gradually into an aqueous solution of the two othermonomers, so as to guarantee the homogeneous distribution of the —COOHgroups in the microgels that precipitate.

At the polymerization temperature, the polymer formed is hydrophobic andprecipitates in the aqueous reaction medium in the form of sphericalparticles, the presence of the crosslinker OEGDA during thepolymerization makes it possible to set the particles in this sphericalshape by creating crosslinking points.

The microgels of the invention have the advantage of being ofhomogeneous structure, since the —COOH groups and the crosslinkingpoints are uniformly distributed throughout their volume.

The microgel films are advantageously prepared by a process of drying orevaporating solvent at 20° C., for example by starting from a colloidaldispersion of monodisperse microgels at a weight concentration that mayvary from 1.4 to 5 wt % in water.

According to this process, at least a first volume of solution may beleft to dry until the complete evaporation of the water at ambienttemperature. This step may be repeated several times in order to obtaina film composed of several layers of monodisperse microgels and having athickness that may vary between 350 and 450 micrometers in the drystate.

The invention also relates to i) a cosmetic or pharmaceutical productconsisting of or containing the microgels as described above andoptionally at least one compound chosen from the group consisting ofsurfactants, oils, biologically active products, pigments and dyes, 2) akit comprising a magnet and a cosmetic product containing microgels thatis described above and that comprises magnetic nanoparticles, saidmagnet and said product being packaged together, iii) a cosmetic makeupor care process that consists in applying to the skin microgels or acosmetic product described above, iv) a thin-film comprising at leastone layer of microgels or of hybrid microgels described above, and v)the uses thereof in various fields of application such as optics,electronics, sensors, cosmetics, pharmacy and medical diagnosis.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 presents the chemical structures of the monomers used for thesynthesis of the biocompatible microgels of the invention.

FIG. 2 is a synthetic scheme of the pH-responsive andtemperature-responsive biocompatible microgels based onpoly(MEO₂MA-co-OEGMA-co-MAA) of the invention.

FIG. 3 is a scheme for preparing γ-Fe₂O₃ particles.

FIGS. 4 and 5 are schematic representations respectively of the 1^(st)and of the 2^(nd) synthesis step of the process for preparing hybridmicrogels according to the invention containing γ-Fe₂O₃ particles.

FIG. 6 represents a scheme of the process for forming films of microgelsaccording to the invention.

FIG. 7 represents an assembly for characterizing the electromechanicaleffect of the films of microgels of the invention.

FIG. 8 is a schematic representation of the period of compression andrelaxation of a film de microgels of the invention.

FIG. 9 represents the diagram of a compression and relaxation program ofmicrogels of the invention.

FIG. 10 is an image of films of microgels of the invention in the drystate and swollen in solution.

FIG. 11 is an image of a dry film of hybrid microgels of the inventioncontaining γ-Fe₂O₃ nanoparticles taken at various viewing angles.

FIG. 12 is an image of a dry film of hybrid microgels of the inventioncontaining γ-Fe₂O₃ nanoparticles taken on a light surface and on a darksurface,

FIG. 13 is an image of a dry film of hybrid microgels of the inventioncontaining γ-Fe₂O₃ nanoparticles with and without magnet.

FIG. 14 depicts Table 1, which shows compositions and morphologies ofmicrogels used to prepare films in Example 4.

The invention is also illustrated by the following examples.

EXAMPLE 1 Synthesis of a Microgel Based on Poly(Oligo(EthyleneGlycol)Methacrylate) According to the Invention

The following monomers were used: di(ethylene glycol) methyl ethermethacrylate (M(EO)₂MA, Mn 250 g.mol⁻¹), oligo(ethylene glycol) methylether methacrylate (denoted OEGMA hereinafter, Mn 475 g.mol⁻¹), andmethacrylic acid (MAA). The crosslinking agent was oligo(ethyleneglycol) diacrylate (OEGDA, Mn 250 g.mol⁻¹).

Experimental Protocol:

0.966 g of MEO₂MA (5.14×10⁻³ mol), 0.272 g of OEGMA (5.73×10⁻⁴ mol) and0.029 g of OEGDA (1.17×10⁻⁴ mol) are introduced into a volume of 57.5 mLof water and left under magnetic stirring until the monomers havecompletely dissolved. The mixture is then filtered and introduced into athree-necked flask having a volume of 250 mL that is equipped with amechanical stirrer before being degassed under nitrogen for 45 min withmechanical stirring (150 rpm). An aqueous solution of MAA (0.026 g,3.05×10⁻⁴ mol dissolved in 2 mL of water) is then introduced into thereaction medium. The mixture is left at 70° C. for 20 min beforeintroducing an aqueous solution of potassium persulfate (KPS, 0.0143 gdissolved in 2.5 mL of water) previously degassed under nitrogen. Theaddition of KPS makes it possible to initiate polymerization and thereaction medium is left under mechanical stirring (50 rpm) at 70° C. for6 h.

The polymerization is then stopped by addition of oxygen and left tocool to ambient temperature. The microgels are then separated from thereaction medium by centrifugation (10 000 rpm, 30 min) and the reactionmedium is replaced by pure water (of milliQ grade); the step is repeatedfive times.

The final solution is then composed of a colloidal dispersion ofP(MEO₂MA-co-OEGMA-co-MAA) microgels in the aqueous phase, thisdispersion is kept at ambient temperature.

Property of the Microgel

The synthesis of the microgels was characterized by kinetic monitoringof the monomers using proton nuclear magnetic resonance (¹H NMR)spectroscopy. A complete conversion of the monomers and also ahomogeneous composition of the microgels, with a homogeneousdistribution of the crosslinking points and of the methacrylic acidunits, are observed.

The final yield of crosslinked microgel was analyzed by solids contentof the reaction medium and makes it possible to determine a yield of 70wt % of crosslinked microgel.

The content of methacrylic acid incorporated was determined by acid-basetitration of the purified microgels. The pH-responsive nature of themicrogels in aqueous solution and also the incorporation of 70 mol % ofthe initial MAA monomer were able to be verified.

The microgels were observed by transmission electron microscopy (TEM)and their sizes were determined by dynamic light scattering. Themicrogels observed are monodisperse, with a size of 400 nm in the driedstate and that may range up to 1000 nm in the wet state.

EXAMPLE 2 Preparation of Solutions of a Microgel Based onPoly(Oligo(Ethylene Glycol) Methacrylate)

1.2 mL of a solution of microgels prepared according to Example 1(containing 15 g.L⁻¹ of microgels) are dispersed in 10 mL of a solutionof pure water (milliQ grade). The pH of the dispersion is adjusted byaddition of a 0.1 mol.L⁻¹ solution of hydrochloric acid or of potassiumhydroxide. The mixture is left under magnetic stirring until the pH hasstabilized. The size of the microgels in solution is measured by dynamiclight scattering and the temperature of the solution is controlledduring the analysis.

By studying the size of the microgels in solution by dynamic lightscattering, it was possible to evaluate the impact of the pH and of thetemperature of the medium on the capacity of the microgels to swell orto shrink in water.

The microgels are responsive to pH variations of the medium, changingfrom a size of 400 nm at pH<5.5 to a size of 1000 nm at pH>6.0.

The microgels are temperature-responsive and change from a swollen stateat 20° C. to a shrunken state at high temperature. The shrinkagetemperature depends on the pH (35° C. at pH<6.0 and 55° C. at pH>7.0).Finally, the volume of the swollen microgel at 20° C. decreases up to 3times relative to its initial volume when the temperature goes beyondthe shrinkage temperature.

EXAMPLE 3 Preparation of a Microgel Based on Poly(Oligo(Ethylene Glycol)Methacrylate) Containing Magnetic Nanoparticles

Synthesis of the maghemite γ-Fe₂O₃ nanoparticles

The reactants used are: ferrous chloride tetrahydrate (FeCl₂.4H₂O),ferric chloride hexahydrate (FeCl₃.6H₂O), 28-30% w/w ammonium hydroxide(NH₄OH), iron nitrate (Fe^(III)(NO₃)₃.9H₂O), 36% v/v hydrochloric acid(HQ) and nitric acid (HNO₃).

The maghemite nanoparticles used during this study were synthesized bycoprecipitation of the metal salts (Fe^(II) and Fe^(III)). This methodof synthesis consists in forming nanoparticles of magnetite (Fe₂O₃) bycoprecipitation of ferrous chloride (FeCl₂) and ferric chloride (FeCl₂)in a basic medium by addition of ammonium hydroxide (NH₄OH). Themagnetite is then oxidized to form the maghemite (γ-Fe₂O₃) variety. Theoxidation of the magnetite to maghemite makes it possible to establishpH-responsive hydroxyl functions at the surface of the nanoparticles,these functions having a point of zero charge at a neutral pH (pH≈7.2).Thus, at acidic or basic pH values, these nanoparticles have a colloidalstate in the aqueous phase by electrostatic repulsion of anionic charges(at basic pH) or cationic charges (at acidic pH). This is a versatilemethod for synthesizing magnetic nanoparticles that are stabilized inthe aqueous phase, commonly referred to as “cationic ferrofluids” or“anionic ferrofluids” depending on the pH of stabilization.

Experimental Protocol

Step 1: Formation of the Magnetite

12.2 g of ferric chloride hexa hydrate FeCl₃.6H₂O (0.0451 mol) areintroduced into a 3 L beaker containing 500 mL of pure water. 4.49 g offerrous chloride tetrahydrate FeCl₂.4H₂O (0.0226 mol) are dissolved in24.3 mL of a 1.5 mol.L⁻¹ solution of hydrochloric acid (HCl) is added tothe 3 L beaker and everything is left mixing under gentle mechanicalstirring (initial Fe^(II)/Fe^(III) ratio=0.5). A volume V=43 mL of28/30% w/w ammonium hydroxide is then added to the beaker with vigorousmechanical stirring and at ambient temperature. The addition of ammoniumhydroxide leads to the formation of flocculated magnetites (Fe₂O₃) inbasic aqueous solution (pH>10), the magnetite flocs are then left tosettle under the effect of a magnetic attraction generated by apermanent magnet, then the supernatant is removed and replaced by purewater (milliQ grade). The washing step is repeated twice in order toremove the excess ammonium hydroxide.

Step 2: Desorption of the Ammonium Counterions and Surface Oxidation

After the successive steps of washing the magnetite, a volume V=28.6 mLof a 2 mol.L⁻¹ aqueous solution of nitric acid HNO₃ is added to themagnetite flocs and is left under mechanical stirring for 30 min inorder to treat the surface of the magnetite particles.

The addition of nitric acid makes it possible to acidify the medium andto induce a desorption of the excess ammonium NH₄ ⁺ counterions at thesurface of the nanoparticles by ion exchange with the nitrate NO₃ ⁻ions. The oxidation of the particles at the surface also makes itpossible to dissolve the ferrous ions that have not precipitated andthat are present at the surface of the nanoparticles.

The surface-treated magnetite flocs are left to settle under a permanentmagnet, then the supernatant is removed and replaced by pure water, thisstep is repeated twice.

Step 3: Oxidation of the Core of the Nanoparticles

After the successive steps of washing the surface-treated magnetites, avolume V=85.7 mL of a freshly prepared 0.33 mol.L⁻¹ solution of ferricnitrate Fe^(III)(NO₃)_(3.9)H₂O is added at boiling to the magnetiteflocs and is left under reflux and under mechanical stirring for 45 min.

The introduction of the Fe³⁺ ions by the ferric nitrate makes itpossible to oxidize the Fe^(II) of the particles thus forming themaghemite γ-Fe₂O₃ variety. After complete oxidation of the particles,the maghemite floc is left to settle under permanent magnet and thesupernatant is removed then replaced by pure water, the operation isrepeated twice.

Step 4: “Peptization” of the Magnetite Nanoparticles

A volume V=28.6 mL of a 2 mol.L⁻¹ solution of nitric acid HNO₃ is addedto the maghemite floc and left at ambient temperature and undermechanical stirring for 30 min. The addition of nitric acid makes itpossible to introduce hydronium H⁺ ions at the surface of the maghemite.The cationic maghemite floc is left to settle then washed three timeswith acetone. A volume V=70 mL of water is then added to thenanoparticles enabling a “peptization” of the nanoparticles in thewater, the dispersion of nanoparticles is then stabilized byelectrostatic repulsion of positive charges at the surface of thenanoparticles. Lastly, the residual acetone is removed by evaporationunder vacuum at 40° C.

Synthesis of P(MEO₂MA-Co-OEGMA-Co-MAA)/γ-Fe₂O₃ Hybrid Microgels

The hybrid microgels are synthesized by simple mixing of an aqueousdispersion of P(MEO₂MA-co-OEGMA-co-MAA) microgels with a dispersion ofmaghemite nanoparticles that is stabilized at pH 2 (nanoparticles withcationic charges). The encapsulation of the nanoparticles within themicrogels is carried out in 2 steps:

-   -   A first step consists in adding the cationic nanoparticles to a        solution of microgels dispersed at pH 3 and at ambient        temperature. These mixing conditions make it possible to retain        the cationic charge at the surface of the γ-Fe₂O₃ nanoparticles.        The nanoparticles will preferentially interact with the        microgels owing to the carboxylic acid groups resulting from the        methacrylic acid units contained within the microgels.        Specifically, the carboxylic acid groups have the ability to be        adsorbed at the surface of particles of metal oxide such as iron        oxide and furthermore the positive charge at the surface of the        nanoparticles enables a favored interaction. In this sense, upon        addition of γ-Fe₂O₃ nanoparticles, the latter will        preferentially be located within the microgels (step summarized        in FIG. 4).    -   A second step consists in increasing the pH of the medium        (microgels+nanoparticles) starting from pH 3 up to pH 7.5. This        rise in the pH induces: 1) A destabilization of the cationic        γ-Fe₂O₃ nanoparticles within the mixture. Specifically, since        the nanoparticles have a point of zero charge at neutral pH        (isoelectric point=7.2), the latter flocculate at this pH due to        lack of electrostatic repulsion. 2) The creation of negative        charges within the microgels derived from the carboxylic acid        (COOH) functions in the form of carboxylate (COO⁻) groups. The        concomitance of these two phenomena makes it possible to anchor        the magnetic nanoparticles within the microgel and to improve        the stability of the hybrid microgels owing to the negative        charges of the carboxylate functions (step summarized in FIG.        5).

Experimental Protocol

A volume of 40 mL of an aqueous dispersion of P((MEO₂MA-co-OEGMA-co-MAA)microgels having a weight concentration of 1.45 g.L⁻¹ is introduced intoa 100 mL round-bottomed flask and left under magnetic stirring, the pHof the dispersion is adjusted to 3.0 by addition of a 0.1 mol.L⁻¹solution of nitric acid (HNO₃). Next, a volume of 10 mL of a dispersionof cationic magnetite nanoparticles at pH 3 having a weightconcentration of 1.34 g.L⁻¹ is added dropwise to the mixture at ambienttemperature and under magnetic stirring, this corresponds to an amountof nanoparticles per hybrid microgels of ˜18.8%. The reaction mixture isleft under stirring and at ambient temperature for 12 h. The pH of thereaction mixture is then increased by dropwise addition of a 0.5 mol.L⁻¹solution of potassium hydroxide (KOH). Finally, the hybrid microgels areseparated from the reaction medium by centrifugation (5000 rpm, 20 min)and the reaction medium is replaced by pure water (of milliQ grade). Thefinal solution is then composed of a colloidal dispersion ofP((MEO₂MA-co-OEGMA-co-MAA) microgels in water, this dispersion is keptat ambient temperature. Various syntheses have been carried out byvarying the theoretical weight fraction of nanoparticles per hybridmicrogel between 0 and 33%.

Property of γ-Fe₂O₃/P(MEO₂MA-Co-OEGMA-Co-MAA) Hybrid Microgels

The hybrid microgels were characterized in the dry state by transmissionelectron microscopy (TEM) and in the wet state by dynamic lightscattering. The hybrid architecture of the microgels was demonstrated byTEM, the observation of the microgels in the dry state makes it possibleto reveal the good encapsulation of the magnetic nanoparticles withinthe microgels which are not expelled during the drying treatment. Thecontent of nanoparticle fillers encapsulated was determined bythermogravimetric analysis, the analysis confirms a quantitative andsignificant encapsulation of the nanoparticles (filler contents testedranging from 0 to 33 wt % of nanoparticles per hybrid microgel). Thetemperature-responsive properties of the hybrid microgels in aqueoussolution at neutral pH are also demonstrated with a shrinkage of thehybrid microgels which change from 1000 nm at 20° C. to 450 nm with ashrinkage temperature of 37° C. This shrinkage at neutral pH takes placeregardless of the magnetic nanoparticle filler content.

EXAMPLE 4 Films of Microgels

The compositions of microgels summarized in Table 1 of FIG. 14 are usedto prepare the films.

The films are prepared by a drying process presented in FIG. 6, startingfrom a colloidal dispersion of monodisperse microgels (having a sizethat may vary between 500 and 1000 μm in solution) having a weightconcentration of microgels that varies from 1.4 to 5 wt % in water(solution 1). A constant volume of solution is introduced into a plasticmold and left to dry until the water has completely evaporated (step 1from FIG. 6). The film remaining at the bottom of the mold is thencomposed of several layers of monodisperse and completely dry microgels(having a size that may vary between 350 and 450 μm in the dry state).The film is carefully recovered and reintroduced into an aqueoussolution (solution 2). Various parameters are varied: 1.) The weightconcentration of dispersion from 1.4 to 5 wt % makes it possible to varythe swollen film thickness (end of step 3: thickness from 200 μm to 1000μm). 2.) The pH of solution 2 is varied between 5.5 and 7.5.

Experimental Protocol: Formation of the Films of Temperature-ResponsiveMicrogels Based on Poly(Oligo(Ethylene Glycol) Methacrylate)

A volume of 5 mL of a colloidal dispersion of microgels at a weightconcentration of 1.4 to 5 wt % is introduced into a plastic mold andleft to dry at a temperature of 32° C. (+/−2° C.). After completeevaporation of the solvent, the film is carefully recovered thenintroduced into an aqueous solution and left to swell at ambienttemperature.

The recovered films were observed by atomic force microscopy in the drystate and characterized using a rheometer in the wet state (end of step3 of FIG. 6). The microgels form an elastic film composed of severallayers of microgels (step 2) and this being irrespective of thecomposition of the microgels (microgels 1 to 5 in table 1). Conversely,the microgels lose their mechanical properties when they are swollen inwater but do not re-disperse in solution.

Microgels 1 and 2: the film thickness is varied from 200 to 1000 μm, themultiplication of the layers of microgels does not modify the “filmformation” phenomenon and the films keep their elasticity in the drystate.

Microgels 3, 4 and 5: A thickness of the order of 300 μm (swollen filmsin step 3) were studied in the case of the hybrid microgels. Theaddition of nanoparticles does not modify the film-forming properties ofthe microgels. On the contrary, the mechanical properties of the filmsare greatly improved in the wet state.

Evaluation of the Electromechanical Properties of the Films

1. Characterisation of the Electromechanical Properties of the Films

The electromechanical properties of the films of microgels were studied.This is a question of demonstrating the capacity of the microgels togenerate an electric current when a pressure is exerted on thesemicrogels. More particularly, the idea of the invention is to generatean electric current by pressing the material at the surface of asubstrate. This electric potential may be generated from a materialhaving ionic functions attached covalently (or polyelectrolytematerial). Specifically, since the ionic groups are attached in themicrogel, only the counterions of each carboxylate group have a mobilityin the microgel. When a unidirectional pressure/deformation is exertedon these polyelectrolyte microgels, the mobility of the counterions isfavored, thus creating a polarization between the positive charges ofthe mobile counterions and the negative charges of the attachedcarboxylate groups. This ionic gradient results in an electric potentialat the interface. Thus, the presence of ionizable functions in themicrogel would make it possible to create a polarization within thematerial and to generate an electric potential.

An assembly is used in order to demonstrate the electromechanicalproperties of the films. For this, an Anton Paar MCR301 rheometer isused in plate-plate geometry within which two flat and conductiveelectrodes based on indium tin oxide or ITO (entity 1. from FIG. 7) areattached on either side of the geometry. The lower electrode is fixedand the upper electrode is removable. A wet film of microgels (entity 3.from FIG. 7) is deposited on the surface of the lower electrode and theupper electrode is lowered in order to exert a compression of forceF_(N) on the film. By controlling the distance between the twoelectrodes, it is possible to control the crushing force (F_(N)) exertedon the film.

A program of compression/relaxation is carried out in order to vary theforce exerted on the film. Firstly, the initial thickness of wet film(denoted L₀) was determined and the distance between the two electrodeswas gradually reduced by a distance ΔL by lowering the upper electrode.The program is distinguished by a short period of crushing (τ=2 seconds)with a final distance L then a long period of relaxation (τ=20 seconds)with a return to the initial state L₀, everything making it possible tosimulate a “touch-sensitive” type action on the film (FIG. 8).

In the crushing period, a normal force F_(N) (in newtons) is recorded.This force F_(N) is proportional to the crushing thickness (ΔL). Theprogram is arranged as such: the film is compressed to a distanceL=L₀-ΔL with ΔL=(3×) 10%.L₀, then (3×) 20%.L₀, then (3×) 25%.L₀ etc. Anexample of a program used is given in FIG. 9.

Lastly, the upper and lower electrodes are connected to aconverter/amplifier, in order to record the potential difference(denoted E) generated between the two electrodes throughout the program.

2. Study of the Films of Microgels

Films of P(MEO₂MA-Co-OEGMA-Co-MAA) Microgels

The films of P(MEO₂MA-co-OEGMA-co-MAA) biocompatible microgels werecharacterized by varying 3 parameters:

1.) The effect of the multiplication of the compressions: for each film,a compression of the same force is repeated successively (3 times asrepresented in FIG. 9) and the potential of each compression isanalyzed.

2.) Rim thickness: two film thicknesses were tested in order todetermine the impact of the thickness on the ability of the films togenerate an electric potential at the interface (˜200 μm and ˜900-1000μm).

3.) Composition of carboxylic acid functions: the composition of MAAunits was varied from 0 to 3.5 mol % of MAA (microgels 1 and 2) in orderto evaluate the impact of the MAA units on the electric potential.

4.) The pH of the solution in which the films are swollen: the pH makesit possible to vary the amount of ionic functions (COO⁻) within themicrogel. Specifically, the carboxylic acid functions are present in theform of two protonated (COOH) and deprotonated or ionized (COO⁻)species. The proportion of these two species depends on the pH of thesolution with an increase in the ionized species COO⁻ when the pH isincreased (pH 5.5→% COO⁻=0; pH 6.5→% COO⁻=50%; pH 7.5→% COO⁻=75%).

TABLE 1 Summary of the samples studied. Thickness of swollen MAA γ-Fe₂O₃film E_(max) F_(N) Sample (mol %) (wt %) (μm) pH (mV) (N) Effect of thefilm thickness Microgel 2 3.5 0 180 6.5 5.4-11.1 0.38-0.40 Microgel 23.5 0 850 6.5 2.0-5.6  0.30-0.35 Effect of the MAA composition Microgel1 0 0 275 6.5 0.43-0.9  0.30-0.35 Microgel 2 3.5 0 180 6.5 5.4-11.10.38-0.40 Effect of the pH Microgel 2 3.5 0 310 5.5 2.0-9.9  0.7-0.9Microgel 2 3.5 0 180 6.5 5.4-11.1 0.38-0.40 Microgel 2 3.5 0 350 7.55.5-11.2 0.18-0.23 Effect of γ-Fe₂O₃ Microgel 2 3.5 0 180 6.5 5.4-11.10.38-0.40 Microgel 2 3.5 4.7 310 6.5 8.7-12.2 0.65-1.13 Microgel 2 3.59.1 320 6.5 2.4-3.7  1.0-1.2 Microgel 2 3.5 16 180 6.5 3.7-3.8  3.0-3.1

Results:

By observing the change in the electric signal during the compression ofthe films of microgels, an electromechanical effect is demonstrated overall of the films characterized. This electromechanical effect is afunction of the force F_(N) exerted on the films with an electricpotential that increases with the compression force. Furthermore, atrend seems to emerge as a function of the analysis parameters:

-   -   Effect of the repetition of the compressions: the electric        potential recorded is very high during the first compression.        Whilst during the 2^(nd) and 3^(rd) compression, the potential        generated is lower. This first observation may be due to a        significant movement of the ions in the first compression of the        film creating a high instantaneous electric potential (˜12 mV).        After a relaxation time of 20 s, the following compressions of        the same force do not appear sufficient to bring about this same        movement of the ions with a generated potential that decreases.    -   Effect of the film thickness: the electric potential generated        by the compression of the films of different thicknesses shows a        weak electromechanical effect when the film is too thick        (E=2-5.6 mV for F_(N,max)=0.35 N). Conversely, a greater        electromechanical effect is seen when the film thickness is        small ranging from 11 to 5 mV for forces F_(N) of 0.38 to 0.4 N.        Too large a thickness would not therefore make it possible to        have a sufficient impact on the mobility of the ions. (cf.        Table 1. Effect of the film thickness)    -   Composition of carboxylic acid functions: the presence of        methacrylic acid appears to improve the electromechanical        properties of the films. Specifically, the films appear more        sensitive to the compression effects with an electric potential        measured for weak forces (11-5 mV at 0.4 N with MAA versus 1-0.5        mV at 0.4 N without MAA). Furthermore, the measurement made at        pH 6.5 highlights the importance of the ionized carboxylate        groups derived from the MAA units (50% of ionized MAA group) on        the sensitivity of the films of microgels. (cf. Table 1. Effect        of the MAA composition)    -   The pH of the solution from 5.5 to 7.5 on the films of microgels        of the same composition does not appear to modify the electric        potential value of the films but when the pH of the solution is        increased, the loss of the electric potential in the face of the        compression repetitions appears to be reduced. Specifically, at        pH 5.5, the repetition of the compression makes the electric        potential drop to 2 mV whereas at a higher pH, the potential        drops to 5.4 mV. This is probably due to the increase in the        proportion of the ionized carboxylate functions (%        COO_(pH5.5)=0%; % COO_(pH6.5)=50%; % COO_(pH 7.5)=75%),        increasing the polarization capacity of the microgels that form        the film. The films are then more sensitive when the pH is        increased, (cf. Table 1. Effect of the pH)

Films of P(MEO₂MA-Co-OEGMA-Co-MAA)/γ-Fe₂O₃ Hybrid Microgels

The films of hybrid microgels were characterized at pH 7.5 and werecompared to a film of microgels without magnetic nanoparticles (NPs). Afilm of microgels without nanoparticles has a maximum potential of 6 mVfor a compression force F_(N)=0.4 N. For the films of microgels withnanoparticles, the potential generated depends on the amount ofnanoparticles incorporated:

-   -   For 5 wt % of magnetic nanoparticles incorporated, the        nanoparticles have no effect on the electric potential generated        and the response of the film to the compressions is 6-7 mV.    -   For 9 and 17 wt % of magnetic nanoparticles incorporated, a        reduction of the electric potential, which reaches 2.5 mV        irrespective of the compression force, is observed. This loss of        electric potential may be attributed to the reduction of charges        derived from the carboxylic acid units at pH 7.5 since they        already interact with the NPs. Specifically, the incorporation        of the nanoparticles takes place by adsorption of the latter at        the ionic sites (COO⁻) contained in the microgels. This        adsorption appears to reduce the fraction of ionic sites still        available within the microgel and thus to reduce the        polarization capacity of the microgels. An amount of 5 wt % of        nanoparticles incorporated does not influence the        polyelectrolyte behavior of the hybrid films (cf. Table 1.        Effect of γ-Fe₂O₃).

Optical Properties of the Microgels

Besides the electromechanical properties, the films of microgels aredistinguished by their optical properties, linked to the ability ofthese films to diffract light. A disparity is observed as a function ofthe composition of the films:

Films of P(MEO₂MA-Co-OEGMA-Co-MAA) Microgels

During the drying of a colloidal dispersion of microgels withoutnanoparticles, the films formed are transparent in the dry state andiridescent in the wet state (FIG. 10). It appears that during theswelling of the microgels, the diameter and the distance between theparticles favor a diffraction of light in the visible region, thisdiffraction is demonstrated by the observation of photonic crystals.

Films of P(MEO₂MA-Co-OEGMA-Co-MAA)/γ-Fe₂O₃ Hybrid Microgels

During the drying of a colloidal dispersion of microgels, a film that istransparent and colored in the dry state is obtained which hasiridescent properties in reflection at very small viewing angles. Thematerial is then brown (color due to the magnetic nanoparticles) whenviewed at 90° and iridescent when viewed at smaller angles (FIG. 11).

The photonic properties are visible in particular in reflection (on darkbackground) and very little in transmission (on light background) asseen in FIG. 12.

Mechanical and Magnetic Properties of the Hybrid Films

Besides the film formation properties of the hybrid microgels and theiroptical properties, the addition of magnetic nanoparticles also makes itpossible to orient the microgels during the drying. FIG. 13 clearlyillustrates these properties since it is possible to concentrate themicrogels during the drying at a precise point by application of amagnetic field (in our case the magnet was placed underneath thedispersion). The drying makes it possible, on the one hand, to seteverything at a targeted point and, on the other hand, to modify thetint of the final film via a localized concentration of the hybridmicrogels while retaining the iridescent properties in reflection(Solution dried with magnet, FIG. 13).

The invention claimed is:
 1. Microgels obtained via precipitationpolymerization of at least three monomers in an aqueous phase, in thepresence of a crosslinking agent, said monomers being: di(ethyleneglycol) methyl ether methacrylate M(EO)₂MA, an oligo(ethylene glycol)methyl ether methacrylate having the formula (M(EO)_(n)MA) wherein nranges from 3 to 12, and methacrylic acid.
 2. The microgels as claimedin claim 1, characterized in that the crosslinking agent is selectedfrom the group consisting of oligo(ethylene glycol) diacrylatecomprising from 1 to 10 ethylene glycol units, 1,3-butanedioldiacrylate, 1,4-butanediol diacrylate, 1,6-hexanediol diacrylate,pentaerythritol diacrylate monostearate, glycerol 1,3-diglycerolatediacrylate, neopentyl glycol diacrylate, poly(propylene glycol)diacrylate, 1,6-hexanediol ethoxylate diacrylate, trimethylolpropanebenzoate diacrylate, N,N-divinylbenzene, N,N-methylenebisacrylamide,N,N-(1,2-dihydroxyethylene)bisacrylamide, poly(ethylene glycol)diacrylamide, allyl disulfide, bis(2-methacryloyl)oxyethyl disulfide andN,N-bis(acryloyl)cystamine.
 3. The microgels according to claim 1,wherein the oligo(ethylene glycol) methyl ether methacrylate has a Mnbeing 475 g.mol-1.
 4. The microgels according to claim 1, wherein thecrosslinking agent is a oligo(ethylene glycol) diacrylate (OEGDA)comprising from 4 to 5 ethylene glycol units.
 5. The microgels accordingto claim 1, wherein the crosslinking agent represents from 1 to 5 mol %of the total number of moles of the three monomers.
 6. The microgelsaccording to claim 1, wherein the molar ratio between M(EO)₂MA andM(EO)_(n)MA is between 1:1 and 20:1.
 7. The microgels according to claim1, wherein M(EO)₂MA represents 80 to 90 mol % of the total number ofmoles of the three monomers, M(EO)_(n)MA represents 5 to 15 mol % of thetotal number of moles of the monomers and methacrylic acid represents0.1 to 10 mol % of the total number of moles of the monomers, the sum ofthese three contents being equal to 100%.
 8. The microgels according toclaim 1, wherein the mean size of the microgels in a dry state may rangefrom 100 to 1000 nm.
 9. The microgels according to claim 1, wherein thehydrodynamic radial distribution function of the microgels measured atan angle of 60° and at a temperature of 20° C., is less than 1.1.
 10. Acosmetic or pharmaceutical composition comprising the microgels asclaimed in claim 1, and at least one compound selected from the groupconsisting of surfactants, oils, biologically active products, pigmentsand dyes.
 11. The microgels according to claim 6, wherein the molarratio between M(EO)₂MA and M(EO)_(n)MA is between 5:1 and 10:1.